Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant.
High affinity antigen-specific T cells play a critical role during protective immune responses. Epitope enhancement can elicit more potent T cell responses and can subsequently lead to a stronger memory pool; however, the molecular basis of such enhancement is unclear. We used the consensus peptide-binding motif for the Major Histocompatibility Complex molecule H-2K(b) to design a heteroclitic version of the mouse hepatitis virus-specific subdominant S598 determinant. We demonstrate that a single amino acid substitution at a secondary anchor residue (Q to Y at position 3) increased the stability of the engineered determinant in complex with H-2K(b). The structural basis for this enhanced stability was associated with local alterations in the pMHC conformation as a result of the Q to Y substitution. Recombinant viruses encoding this engineered determinant primed CTL responses that also reacted to the wildtype epitope with significantly higher functional avidity, and protected against selection of virus mutated at a second CTL determinant and consequent disease progression in persistently infected mice. Collectively, our findings provide a basis for the enhanced immunogenicity of an engineered determinant that will serve as a template for guiding the development of heteroclitic T cell determinants with applications in prevention of CTL escape in chronic viral infections as well as in tumor immunity.
Butler
Noah S
NS
Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.
Theodossis
Alex
A
Webb
Andrew I
AI
Nastovska
Roza
R
Ramarathinam
Sri Harsha
SH
Dunstone
Michelle A
MA
Rossjohn
Jamie
J
Purcell
Anthony W
AW
Perlman
Stanley
S
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D016525:Antigenic Modulation / Q000235:genetics; D018352:Coronavirus Infections / Q000276:immunology* / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics*; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D006517:Murine hepatitis virus / Q000235:genetics / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D055550:Protein Stability; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000502:physiology; D013696:Temperature; D013816:Thermodynamics
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D016056:Immunodominant Epitopes